Carbonic anhydrase inhibitors. Regioselective synthesis of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII.

Abstract

A series of 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamide (2-16) have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is the cytosolic ubiquitous CA I and II, and cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed inhibition constants in the range of 1.09-12.1 microM, against hCA II in the range of 50.5-172 nM, against hCA IX in the range of 5.2-118 nM, and against hCA XII in the range of 8.7-381 nM, respectively. Compounds 2, 3, 5-9, 11, 13 and 14 showed excellent hCA IX inhibitory efficacy, with K(I)s = 5.2-11.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM). Compounds 2, 3, 5-9, 11 and 13 were also very effective hCA XII inhibitors (K(I)s = 8.7-45.2 nM) which are comparable or more effective than those clinically used EZA and DCP (K(I)s = 22 and 50 nM), respectively.